There is convincing evidence from family, adoption and twin research for the importance of familial factors in the development of alcohol dependence. Laboratory studies have been conducted with offspring of alcoholics who have not yet themselves developed the disorder in an effort to identify markers associated with the increased risk of alcoholism. Differences in alcohol sensitivity have been found as a function of familial alcoholism history. More recently, research has examined the generalization to other drug classes of this differential sensitivity associated with familial alcoholism. Epidemiological evidence from our own research and others' has shown that family history positive youth (FHP) use marijuana at a greater frequency, report an earlier age of first use of marijuana, and report more problems as a result of drug use than family history negative youth (FHN). This research project examines the role of a family history of alcoholism in modulating responses to marijuana, employing controlled dosing procedures. Subjects include males and females aged 18-25 years with a high density of familial alcoholism and a matched comparison group with no familial alcoholism. We are currently examining the role of familial alcoholism as a determinant of the dose-effects of smoked marijuana. Ethanol is administered as a positive control to allow an explict comparison of the magnitude of family history group differences in response to these two drugs. On each session day after baseline measures are taken, subjects consume a drink (alcohol 0.75 g/kg or placebo) and smoke two cigarettes (THC 1.77%, 3.9% or placebo); active drug is administered only by one route. Thus, drug conditions are: alcohol 0.75 g/kg/placebo THC, placebo alcohol/1.77% THC, placebo alcohol/3.9% THC, and placebo alcohol/placebo THC. Four response dimensions are studies: physiological, psychomotor, subjective and behavioral. Of particular interest are smoking topography measures such as puff volume, duration and patterning, as well as neuroendocrine measures including ACTH, beta-endorphins, prolactin, and growth hormone.